2018 MACH MRFF
Rapid Applied Research Translation
Successful Grants & Fellowships
Prof Ingrid Scheffer AO
MACH Partners: Austin Health, Florey Institute of Neuroscience and Mental Health, Royal Children's Hospital, The University of Melbourne, Walter and Eliza Hall Institute
Project title: Developing precision medicine for the developmental and epileptic encephalopathies
Summary: This project explores which genes are involved in epileptic encephalopathies – severe epilepsies that begin in infancy and childhood with devastating outcomes – and, of those, which ones might provide opportunities for new therapies. Stem cells derived from the patient group will be utilised to safely test new pharmaceutical treatments. This project will have significant impact for epilepsy patients and families, enabling a specific diagnosis for affected individuals in whom a genetic mutation is identified.
About Prof Scheffer's Research Project
What is the problem you're trying to solve?
Epileptic encephalopathies (EEs) are severe epilepsies that begin in infancy and childhood with devastating outcomes. Children have uncontrolled epilepsy, severe to profound developmental impairment, and other conditions such as autism spectrum disorder and high mortality risk. For most children there is a genetic cause and in 50% of cases the gene involved has been identified. But the problem is very complex and overall more than 100 genes are involved.
About this research translation project
This project will expand on an existing patient group of more than 700 to help understand which genes cause their disease and, of those, which ones might provide opportunities for new therapies. Stem cells derived from the patient group will be utilised to safely test new pharmaceutical treatments. There are elements of how epilepsy works that are well understood. This project will also investigate the use of existing drugs that have been developed for other conditions to determine their value in treating epilepsy. Because these drugs are already in the market and are safe, they can be rapidly repurposed if useful. Importantly, the research team already has strong working relationships with the families of the children involved – a critical factor in successful trials of this type.
With an aim to end the 'diagnostic odyssey' for patients with developmental and epileptic encephalopathies and their families through providing a definitive diagnosis, the project has led to improvements in:
Patients in the study received their first diagnosis of the cause of their severe disorder and new genetic markers were discovered for development in the future as diagnostic tools
Whole genome sequencing was validated as a tool to identify new disease mechanisms and the cause in patients with Dravet syndrome of unknown cause
The study has contributed changes in recurrence risk counselling practices to more accurately inform parents of their family planning options
Publications associated with the project:
1.Helbig KL, Lauerer RJ, Bahr JC, Souza IA, et al. De novo pathogenic variants in CACNA1E cause developmental and epileptic encephalopathy with contractures, macrocephaly, and dyskinesias. Am J Hum Genet. 2019; 104: 562. doi: 10.1016/j.ajhg.2019.02.015.
2.Myers KA, McMahon JM, Mandelstam SA, Mackay MT, Kalnins RM, Leventer RJ, Scheffer IE. Fatal cerebral edema with status epilepticus in children with Dravet syndrome: Report of 5 Cases. Pediatrics. 2017; 139: pii: e20161933. doi: 10.1542/peds.2016-1933.
3.Carvill GL, Engel KL, Ramamurthy A, Cochran JN, Roovers J et al. Aberrant inclusion of a poison exon causes Dravet syndrome and related SCN1A-associated genetic epilepsies. Am J Hum Genet. 2018; 103 :1022-1029. doi: 10.1016/j.ajhg.2018.10.023.
4.Bar C…Scheffer IE, Kabashi E, Nabbout R. Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of the literature. Hum Mutat. 2020; 41: 69-80. doi: 10.1002/humu.23915.
5.Berecki G, Bryson A, Terhag J, Maljevic S, Gazina EV, Hill SL, Petrou S. SCN1A gain of function in early infantile encephalopathy. Ann Neurol. 2019; 85: 514-525. doi: 10.1002/ana.25438.
6.Berecki G, Howell KB, Deerasooriya YH, Cilio MR, Oliva MK, Kaplan D, Scheffer IE, Berkovic SF, Petrou S. Dynamic action potential clamp predicts functional separation in mild familial and severe de novo forms of SCN2A epilepsy. Proc Natl Acad Sci USA. 2018; 115: E5516-E5525. doi: 10.1073/pnas.1800077115.
7.Li M, Maljevic S, Phillips AM, Petrovski S, Hildebrand MS, Burgess R, Mount T, Zara F, Striano P, Schubert J, Thiele H, Nürnberg P, Wong M, Weisenberg JL, Thio LL, Lerche H, Scheffer IE, Berkovic SF, Petrou S, Reid CA. Gain-of-function HCN2 variants in genetic epilepsy. Hum Mutat. 2018; 39:202-209. doi: 10.1002/humu.23357.
8.McTague A, Nair U, Malhotra S, Meyer E, Trump N, Gazina EV, Papandreou A, Ngoh A, Ackermann S, Ambegaonkar G, Appleton R, Desurkar A, Eltze C, Kneen R, Kumar AV, Lascelles K, Montgomery T, Ramesh V, Samanta R, Scott RH, Tan J, Whitehouse W, Poduri A, Scheffer IE, Chong WKK, Cross JH, Topf M, Petrou S, Kurian MA. Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy. Neurology. 2018; 90: e55-e66. doi: 10.1212/WNL.0000000000004762.
Download this project summary:
For more information on this project, please contact the MACH office:
(03) 8344 9973